US20110098318A1 - Farnesyl protein transferase inhibitors for treating breast cancer - Google Patents

Abstract

The present invention relates to the use of farnesyl protein transferase inhibitors for preparing pharmaceutical compositions for treating advanced breast cancer.

Description

• The present invention is concerned with the finding that farnesyl protein transferase inhibitors are useful for preparing a pharmaceutical composition for treating advanced breast cancer.
• Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer. A particular group of oncogenes is known as ras which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts. The family of mammalian ras oncogenes consists of three major members (“isoforms”): H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highly related proteins generically known as p21^ras. Once attached to plasma membranes, the mutant or oncogenic forms of p21^ras will provide a signal for the transformation and uncontrolled growth of malignant tumor cells. To acquire this transforming potential, the precursor of the p21^ras oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Therefore, inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, will prevent the membrane attachment of p21^ras and block the aberrant growth of ras-transformed tumors. Hence, it is generally accepted in the art that farnesyl transferase inhibitors can be very useful as anticancer agents for tumors in which ras contributes to transformation.
• It has been estimated that as many as 30-40% of human tumours may contain a ras mutation, with some tumours, such as colon and lung, showing ras mutations in around 50% and 90% of tumours, respectively. K-ras and Ha-ras mutations have been identified in breast cancer tumours, but at low levels (approximately 5%).
• However, although ras mutations are relatively infrequent in breast cancer, there is evidence to suggest that the pathways which ras services may still be deregulated in breast cancer cells (Clark G J and Der C J, Breast Cancer Res. Treat. 1995, 35 (1), 133-144). Recent identification of many of the components of the ras signal transduction pathway has defined a network of protooncogene proteins controlling diverse signalling events that regulate cell growth and differentiation. Mutations that alter the function of any one component of this signal pathway may trigger the same oncogenic events as a mutation of ras itself. Moreover, ras-related proteins, such as TC21/R-Ras2, have been shown to possess the ability to trigger malignant transformation in MCF-10A human breast epithelial cells lines via signalling pathways shared with ras proteins (Clark G. J. et al, Oncogene, 1996, 12(1), 169-76). Also, TC21 protein expression was found to be greatly elevated in 7 of 9 breast tumour lines when compared to untransformed MCF-10A cells.
• Bland et al (Ann. Surg. 1995, 221(6), 706-18) looked at oncogene protein expression as prognostic discriminants for breast cancer. Of the individual oncogenes examined (c-fos, c-myc, Ha-ras and p53), the presence of Ha-ras and c-fos gave the greatest prediction for poor survival.
• Breast cancer is the most common female malignancy and the main cause of death from cancer in women. Each year approximately 30,000 new cases are diagnosed and there are nearly 16,000 deaths in the UK; about 1 in 12 women will develop breast cancer at some time in their life.
• Patients with clinically evident distant metastases are still incurable, although the disease may be controlled for periods longer than 5 or 10 years in some patients. However the median survival of all patients with metastatic disease is approximately 2 to 3 years, and the search for additional effective therapies continues.
• Currently patients with indolent disease, i.e. disease characterised by the presence of bone, soft tissue or non-life threatening visceral metastases are generally treated in the first instance with an endocrine therapy, such as an aromatase inhibitor, anti-oestrogen or progestogen. Depending on their response to that therapy, patients may receive further endocrine treatment before being considered for chemotherapy. Patients with aggressive disease, characterised by widespread symptomatic metastases or extensive visceral involvement, will normally be considered for combination therapy, such as FEC or CAF, as a more rapid response is desirable in these patients. Patients who have oestrogen receptor (ER) negative tumours may also be treated in the first instance with chemotherapy, since hormonal therapy is largely ineffective in this group.
• WO-97/21701 describes the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting (imidazoly-5-yl)methyl-2-quinolinone derivatives of formulas (I), (II) and (III), as well as intermediates of formula (II) and (III) that are metabolized in vivo to the compounds of formula (I). The compounds of formulas (I), (II) and (III) are represented by
• 
• the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein
  the dotted line represents an optional bond;
  X is oxygen or sulfur;
• R¹ is hydrogen, C_1-12alkyl, Ar¹, Ar²C_1-6alkyl, quinolinylC_1-6alkyl, PyridylC_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, amino C_1-6alkyl, or a radical of formula -Alk¹-C(═O)—R⁹, -Alk¹-S(O)—R⁹ or -Alk¹-S(O)₂—R⁹, wherein Alk¹ is C_1-6alkanediyl,
  • R⁹ is hydroxy, C_1-6alkyl, C_1-6alkyloxy, amino, C_1-8alkylamino or C_1-8alkylamino substituted with C_1-6alkyloxycarbonyl;
• R², R³ and R¹⁶ each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, aminoC_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar¹, Ar²C_1-6alkyl, Ar²oxy, Ar²C_1-6alkyloxy, hydroxycarbonyl, C_1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, 4,4-dimethyloxazolyl; or
  • when on adjacent positions R² and R³ taken together may form a bivalent radical of formula
• 
  —O—CH₂—O—  (a-1),
• 
  —O—CH₂—CH₂—O—  (a-2),
• 
  —O—CH═CH—  (a-3),
• 
  —O—CH₂—CH₂—  (a-4),
• 
  —O—CH₂—CH₂—CH₂—  (a-5), or
• 
  —CH═CH—CH═CH—  (a-6);
• R⁴ and R⁵ each independently are hydrogen, halo, Ar¹, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl;
• R⁶ and R⁷ each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, Ar²oxy, trihalomethyl, C_1-6alkylthio, di(C_1-6alkyl)amino, or
  • when on adjacent positions R⁶ and R⁷ taken together may form a bivalent radical of formula
• 
  —O—CH₂—O—  (c-1), or
• 
  —CH═CH—CH═CH—  (c-2);
• R⁸ is hydrogen, C_1-6alkyl, cyano, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylcarbonylC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, carboxyC_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, mono- or di(C_1-6alkyl)-aminoC_1-6alkyl, imidazolyl, haloC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, aminocarbonylC_1-6alkyl, or a radical of formula
• 
  —O—R¹⁰  (b-1),
• 
  —S—R¹⁰  (b-2),
• 
  —N—R¹¹R¹²  (b-3),
• • wherein R¹⁰ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹, Ar²C_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical or formula -Alk²-OR¹³ or -Alk²-NR¹⁴R¹⁵;
    • R¹¹ is hydrogen, C_1-12alkyl, Ar¹ or Ar²C_1-6alkyl;
    • R¹² is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylaminocarbonyl, Ar¹, Ar²C_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, a natural amino acid, Ar¹carbonyl, Ar²C_1-6alkylcarbonyl, aminocarbonylcarbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy, aminocarbonyl, di(C_1-6alkyl)aminoC_1-6alkylcarbonyl, amino, C_1-6alkylamino, C_1-6alkylcarbonylamino, or a radical or formula -Alk²-OR¹³ or -Alk²-NR¹⁴R¹⁵;
      wherein Alk² is C_1-6alkanediyl;
  • R¹³ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy-C_1-6alkyl, Ar¹ or Ar²C_1-6alkyl;
  • R¹⁴ is hydrogen, C_1-6alkyl, Ar¹ or Ar²C_1-6alkyl;
  • R¹⁵ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹ or Ar²C_1-6alkyl;
• R¹⁷ is hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxycarbonyl, Ar¹;
• R¹⁸ is hydrogen, C_1-6alkyl, C_1-6alkyloxy or halo;
• R¹⁹ is hydrogen or C_1-6alkyl;
• Ar¹ is phenyl or phenyl substituted with C_1-6alkyl, hydroxy, amino, C_1-6alkyloxy or halo; and
• Ar² is phenyl or phenyl substituted with C_1-6alkyl, hydroxy, amino, C_1-6alkyloxy or halo.
• WO-97/16443 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IV), as well as intermediates of formula (V) and (VI) that are metabolized in vivo to the compounds of formula (IV). The compounds of formulas (IV), (V) and (VI) are represented by
• 
• the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein
  the dotted line represents an optional bond;
  X is oxygen or sulfur;
• R¹ is hydrogen, C_1-12alkyl, Ar¹, Ar²C_1-6alkyl, quinolinylC_1-6alkyl, pyridyl-C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, mono- or di(C_1-6alkyl)-aminoC_1-6alkyl, aminoC_1-6alkyl,
  • or a radical of formula -Alk¹-C(═O)—R⁹, -Alk¹-S(O)—R⁹ or -Alk'-S(O)₂—R⁹, wherein Alk¹ is C_1-6alkanediyl,
    • R⁹ is hydroxy, C_1-6alkyl, C_1-6alkyloxy, amino, C_1-8alkylamino or C_1-8alkylamino substituted with C_1-6alkyloxycarbonyl;
• R² and R³ each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, amino-C_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar¹, Ar²C_1-6alkyl, Ar²oxy, Ar²C_1-6alkyloxy, hydroxycarbonyl, C_1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl; or
  • when on adjacent positions R² and R³ taken together may form a bivalent radical of formula
• 
  —O—CH₂—O—  (a-1),
• 
  —O—CH₂—CH₂—O—  (a-2),
• 
  —O—CH═CH—  (a-3),
• 
  —O—CH₂—CH₂—  (a-4),
• 
  —O—CH₂—CH₂—CH₂—  (a-5), or
• 
  —CH═CH—CH═CH—  (a-6);
• R⁴ and R⁵ each independently are hydrogen, Ar¹, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl;
• R⁶ and R⁷ each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy or Ar²oxy;
• R⁸ is hydrogen, C_1-6alkyl, cyano, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkyl-carbonylC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, hydroxy-carbonylC_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, mono- or di(C_1-6alkyl)-aminoC_1-6alkyl, haloC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, aminocarbonylC_1-6alkyl, Ar¹, Ar²C_1-6alkyloxyC_1-6alkyl, C_1-6alkylthioC_1-6alkyl;
• R¹⁰ is hydrogen, C_1-6alkyl, C_1-6alkyloxy or halo;
• R¹¹ is hydrogen or C_1-6alkyl;
• Ar¹ is phenyl or phenyl substituted with C_1-6alkyl, hydroxy, amino, C_1-6alkyloxy or halo;
• Ar² is phenyl or phenyl substituted with C_1-6alkyl, hydroxy, amino, C_1-6alkyloxy or halo.
• WO-98/40383 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VII)
• 
• the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
  the dotted line represents an optional bond;
  X is oxygen or sulfur;
  -A- is a bivalent radical of formula
• 
  —CH═CH—  (a-1),
• 
  —CH₂—CH₂—  (a-2),
• 
  —CH₂—CH₂—CH₂—  (a-3),
• 
  —CH₂—O—  (a-4),
• 
  —CH₂—CH₂—O—  (a-5),
• 
  —CH₂—S—  (a-6),
• 
  —CH₂—CH₂—S—  (a-7),
• 
  —CH═N—  (a-8),
• 
  —N═N—  (a-9), or
• 
  —CO—NH—  (a-10);
• • wherein optionally one hydrogen atom may be replaced by C_1-4alkyl or Ar¹;
• R¹ and R² each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, C_1-6alkyloxycarbonyl, aminoC_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar², Ar²-C_1-6alkyl, Ar²-oxy, Ar²-C_1-6alkyloxy; or when on adjacent positions R¹ and R² taken together may form a bivalent radical of formula
• 
  —O—CH₂—O—  (b-1),
• 
  —O—CH₂—CH₂—O—  (b-2),
• 
  —O—CH═CH—  (b-3),
• 
  —O—CH₂—CH₂—  (b-4),
• 
  —O—CH₂—CH₂—CH₂—  (b-5), or
• 
  —CH═CH—CH═CH—  (b-6);
• R³ and R⁴ each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, Ar³-oxy, C_1-6alkylthio, di(C_1-6alkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R³ and R⁴ taken together may form a bivalent radical of formula
• 
  —O—CH₂—O—  (c-1),
• 
  —O—CH₂—CH₂—O—  (c-2), or
• 
  —CH═CH—CH═CH—  (c-3);
• R⁵ is a radical of formula
• 
• • wherein R¹³ is hydrogen, halo, Ar⁴, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxy-C_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS (O)₂C_1-6alkyl;
    • R¹⁴ is hydrogen, C_1-6alkyl or di(C_1-4alkyl)aminosulfonyl;
• R⁶ is hydrogen, hydroxy, halo, C_1-6alkyl, cyano, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, aminoC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkylthioC_1-6alkyl, aminocarbonylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6 alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, C_1-6alkyloxycarbonyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, Ar⁵, Ar⁵-C_1-6alkyloxyC_1-6alkyl; or a radical of formula
• 
  —O—R⁷  (e-1),
• 
  —S—R⁷  (e-2),
• 
  —N—R⁸R⁹  (e-3),
• • wherein R⁷ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar⁶, Ar⁶-C_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical of formula -Alk-OR¹⁰ or -Alk-NR¹¹R¹²;
    • R⁸ is hydrogen, C_1-6alkyl, Ar⁷ or Ar⁷-C_1-6alkyl;
    • R⁹ is hydrogen, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkyloxycarbonyl, C_1-6alkylaminocarbonyl, Ar⁸, Ar⁸-C_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, Ar⁸-carbonyl, Ar⁸-C_1-6alkylcarbonyl, aminocarbonyl-carbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy, aminocarbonyl, di(C_1-6alkyl)aminoC_1-6alkylcarbonyl, amino, C_1-6alkylamino, C_1-6alkylcarbonylamino,
      • or a radical or formula -Alk-OR¹⁰ or -Alk-NR¹¹R¹²;
  • wherein Alk is C_1-6alkanediyl;
    • R¹⁰ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy-C_1-6alkyl, Arg or Arg-C_1-6alkyl;
    • R¹¹ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹⁰ or Ar¹⁰—C_1-6alkyl;
    • R¹² is hydrogen, C_1-6alkyl, Ar¹¹ or Ar¹¹-C_1-6alkyl; and
  • Ar¹ to Ar¹¹ are each independently selected from phenyl; or phenyl substituted with halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl.
• WO-98/49157 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VIII)
• 
• the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
  the dotted line represents an optional bond;
  X is oxygen or sulfur;
• R¹ and R² each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, C_1-6alkyloxycarbonyl, aminoC_1-6alkyloxy, mono- or di(C_1-6alkyl)aminoC_1-6alkyloxy, Ar¹, Ar¹C_1-6alkyl, Ar¹oxy or Ar¹C_1-6alkyloxy;
• R³ and R⁴ each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, Ar¹oxy, C_1-6alkylthio, di(C_1-6alkyl)amino, trihalomethyl or trihalomethoxy;
• R⁵ is hydrogen, halo, C_1-6alkyl, cyano, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, aminoC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6 alkylthioC_1-6alkyl, aminocarbonylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, C_1-6alkyloxycarbonyl, mono- or di(C_1-6alkyl)aminoC_1-6alkyl, Ar¹, Ar¹C_1-6alkyloxyC_1-6alkyl; or a radical of formula
• 
  —O—R¹⁰  (a-1),
• 
  —S—R¹⁰  (a-2),
• 
  —N_R¹¹R¹²  (a-3),
• • wherein R¹⁰ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹, Ar¹C_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical of formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;
    • R¹¹ is hydrogen, C_1-6alkyl, Ar¹ or Ar¹C_1-6alkyl;
    • R¹² is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylaminocarbonyl, Ar¹, Ar¹C_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, Ar¹carbonyl, Ar¹C_1-6alkylcarbonyl, aminocarbonyl-carbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy, aminocarbonyl, di(C_1-6alkyl)aminoC_1-6alkylcarbonyl, amino, C_1-6alkylamino, C_1-6alkylcarbonylamino,
      • or a radical or formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;
      • wherein Alk is C_1-6alkanediyl;
        • R¹³ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy-C_1-6alkyl, Ar¹ or Ar¹C_1-6alkyl;
        • R¹⁴ is hydrogen, C_1-6alkyl, Ar¹ or Ar¹C_1-6alkyl;
        • R¹⁵ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹ or Ar¹C_1-6alkyl;
• R⁶ is a radical of formula
• 
• • wherein R¹⁶ is hydrogen, halo, Ar¹, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxy-C_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, C_1-6alkyloxycarbonyl, C_1-6alkylthioC_1-6alkyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl;
    • R¹⁷ is hydrogen, C_1-6alkyl or di(C_1-4alkyl)aminosulfonyl;
• R⁷ is hydrogen or C_1-6alkyl provided that the dotted line does not represent a bond;
• R⁸ is hydrogen, C_1-6alkyl or Ar²CH₂ or Het¹CH₂;
• R⁹ is hydrogen, C_1-6alkyl, C_1-6alkyloxy or halo; or
• R⁸ and R⁹ taken together to form a bivalent radical of formula
• 
  —CH═CH—  (c-1),
• 
  —CH₂—CH₂—  (c-2),
• 
  —CH₂—CH₂—CH₂—  (c-3),
• 
  —CH₂—O—  (c-4), or
• 
  —CH₂—CH₂—O—  (c-5);
• Ar¹ is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl;
• Ar² is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl; and
• Het¹ is pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl.
• WO-00/39082 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IX)
• 
• or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
• ═X¹—X²—X³— is a trivalent radical of formula
• 
  ═N—CR⁶═CR⁷—  (x-1),
• 
  ═N—N═CR⁶—  (x-2),
• 
  ═N—NH—C(═O)—  (x-3),
• 
  ═N—N═N—  (x-4),
• 
  ═N—CR⁶═N—  (x-5),
• 
  ═CR⁶—CR⁷═CR⁸—  (x-6),
• 
  ═CR⁶—N═CR⁷—  (x-7),
• 
  ═CR⁶—NH—C(═O)—  (x-8), or
• 
  ═CR⁶—N═N—  (x-9);
• • wherein each R⁶, R⁷ and R⁸ are independently hydrogen, C_1-4alkyl, hydroxy, C_1-4alkyloxy, aryloxy, C_1-4alkyloxycarbonyl, hydroxyC_1-4alkyl, C_1-4alkyloxyC_1-4alkyl, mono- or di(C_1-4alky)aminoC_1-4alkyl, cyano, amino, thio, C_1-4alkylthio, arylthio or aryl;
• >Y¹—Y²— is a trivalent radical of formula
• 
  >CH—CHR⁹—  (y-1),
• 
  >C═N—  (y-2),
• 
  >CH—NR⁹—  (y-3), or
• 
  >C═CR⁹—  (y-4);
• • wherein each R⁹ independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyC_1-4alkyl, cyano, carboxyl, C_1-4alkyl, C_1-4alkyloxy, C_1-4alkyloxyC_1-4alkyl, C_1-4alkyloxycarbonyl, mono- or di(C_1-4alky)amino, mono- or di(C_1-4alky)aminoC_1-4alkyl, aryl;
• r and s are each independently 0, 1, 2, 3, 4 or 5;
• t is 0, 1, 2 or 3;
• each R¹ and R² are independently hydroxy, halo, cyano, C_1-6alkyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkylthio, C_1-6alkyloxyC_1-6alkyloxy, C_1-6alkyloxycarbonyl, aminoC_1-6alkyloxy, mono- or di(C_1-6alky)amino, mono- or di(C_1-6alky)aminoC_1-6alkyloxy, aryl, arylC_1-6alkyl, aryloxy or arylC_1-6alkyloxy, hydroxycarbonyl, C_1-6alkyloxycarbonyl, aminocarbonyl, aminoC_1-6alkyl, mono- or di(C_1-6alky)aminocarbonyl, mono- or di(C_1-6alky)aminoC_1-6alkyl; or
• two R¹ or R² substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula
• 
  —O—CH₂—O—  (a-1),
• 
  —O—CH₂—CH₂—O—  (a-2),
• 
  —O═CH═CH—  (a-3),
• 
  —O—CH₂—CH₂—  (a-4),
• 
  —O—CH₂—CH₂—CH₂—  (a-5), or
• 
  —CH═CH—CH═CH—  (a-6);
• R³ is hydrogen, halo, C_1-6alkyl, cyano, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, aminoC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkylthioC_1-6alkyl, aminocarbonylC_1-6alkyl, hydroxycarbonyl, hydroxycarbonylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, C_1-6alkylcarbonylC_1-6alkyl, C_1-6alkyloxycarbonyl, aryl, arylC_1-6alkyloxyC_1-6alkyl, mono- or di(C_1-6alky)aminoC_1-6alkyl;
• or a radical of formula
• 
  —O—R¹⁰  (b-1),
• 
  —S—R¹⁰  (b-2),
• 
  —NR¹¹R¹²  (b-3),
• wherein R¹⁰ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, aryl, arylC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical of formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;
  • R¹¹ is hydrogen, C_1-6alkyl, aryl or arylC_1-6alkyl;
  • R¹² is hydrogen, C_1-6alkyl, aryl, hydroxy, amino, C_1-6alkyloxy, C_1-6alkylcarbonylC_1-6alkyl, arylC_1-6alkyl, C_1-6alkylcarbonylamino, mono- or di(C_1-6alky)amino, C_1-6alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloC_1-6alkylcarbonyl, arylC_1-6alkylcarbonyl, C_1-6alkyloxycarbonyl,
    • C_1-6alkyloxyC_1-6alkylcarbonyl, mono- or di(C_1-6alky)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or C_1-3alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or di(C_1-6alky)aminoC_1-6alkylcarbonyl, or a radical or formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;
  • wherein Alk is C_1-6alkanediyl;
    • R¹³ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxyC_1-6alkyl, aryl or arylC_1-6alkyl;
    • R¹⁴ is hydrogen, C_1-6alkyl, aryl or arylC_1-6alkyl;
    • R¹⁵ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, aryl or arylC_1-6alkyl;
• R⁴ is a radical of formula
• 
• wherein R¹⁶ is hydrogen, halo, aryl, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, mono- or di(C_1-4alky)amino, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylthioC_1-6alkyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl;
  • R¹⁶ may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R¹⁶ when bound to the nitrogen is limited to hydrogen, aryl, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl;
  • R¹⁷ is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, arylC_1-6alkyl, trifluoromethyl or di(C_1-4alky)aminosulfonyl;
• R⁵ is C_1-6alkyl, C_1-6alkyloxy or halo;
• aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl.
• Other useful farnesyl protein transferase inhibitors include Arglabin (i.e.1(R)-10-epoxy-5(S),7(S)-guaia-3(4),11(13)-dien-6,12-olide descibed in WO-98/28303 (NuOncology Labs); perrilyl alcohol described in WO-99/45912 (Wisconsin Genetics); SCH-66336, i.e. (+)-(R)-4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide, described in U.S. Pat. No. 5,874,442 (Schering); L778123, i.e. 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone, described in WO-00/01691 (Merck); compound 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone described in WO-94/10138 (Merck); and BMS 214662, i.e. (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulphonyl)-1H-1,4-benzodiazapine-7-carbonitrile, described in WO 97/30992 (Bristol Myers Squibb) and Pfizer compounds (A) and (B) described in WO-00/12498 and WO-00/12499:
• 
• Unexpectedly, we have now found that a farnesyl protein transferase inhibitor has clinical activity in advanced breast cancer. This effect is especially surprising as treatment with the farnesyl protein transferase inhibitor results in shrinkage of the tumor rather than simply delaying tumor progression. This effect is in contrast to the suggestion in Rowinsky et al, Journal of Clinical Oncology, Vol 17, No. 11 (November), 1999, pages 3631-3652 at page 3646 that tumor growth inhibition or “cytostasis” may be the principal therapeutic effect of FTase inhibitors.
• The present invention is concerned with the use of at least a farnesyl protein transferase inhibitor for the preparation of a pharmaceutical composition for treating advanced breast cancer. The term “advanced breast cancer” is used herein to denote breast cancer which has not responded to previous treatment, or which has recurred following such treatment, and also breast cancer in patients who present with metastatic disease at diagnosis.
• The present invention also concerns a method of treating advanced breast cancer in a mammal, particularly a woman, comprising the step of administering a therapeutically effective amount of a farnesyl protein tranferase inhibitor to said mammal.
• In particular, the present invention is concerned with the use of at least a farnesyl protein transferase inhibitor for the preparation of a pharmaceutical composition for treating advanced breast cancer, wherein said farnesyl protein transferase inhibitor is a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) above, more particularly a compound of formula (I), (II) or (III):
• 
• the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein
  the dotted line represents an optional bond;
  X is oxygen or sulfur;
• R¹ is hydrogen, C_1-12alkyl, Ar¹, Ar²C_1-6alkyl, quinolinylC_1-6alkyl, pyridyl-C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, mono- or di(C_1-6alkyl)-aminoC_1-6alkyl, aminoC_1-6alkyl,
  • or a radical of formula -Alk¹-C(═O)—R⁹, -Alk¹-S(O)—R⁹ or -Alk¹-S(O)₂—R⁹,
  • wherein Alk¹ is C_1-6alkanediyl,
    • R⁹ is hydroxy, C_1-6alkyl, C_1-6alkyloxy, amino, C_1-8alkylamino or C_1-8alkylamino substituted with C_1-6alkyloxycarbonyl;
• R², R³ and R¹⁶ each independently are hydrogen, hydroxy, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, hydroxyC_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, aminoC_1-6alkyloxy, mono- or di(C_1-6alky)aminoC_1-6alkyloxy, Ar¹, Ar²C_1-6alkyl, Ar²oxy, Ar²C_1-6alkyloxy, hydroxycarbonyl, C_1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C_2-6alkenyl, 4,4-dimethyloxazolyl; or
  • when on adjacent positions R² and R³ taken together may form a bivalent radical of formula
• 
  —O—CH₂—O—  (a-1),
• 
  —O—CH₂—CH₂—O—  (a-2),
• 
  —CH═CH—  (a-3),
• 
  —O—CH₂—CH₂—  (a-4),
• 
  —O—CH₂—CH₂—CH₂—  (a-5), or
• 
  —CH═CH—CH═CH—  (a-6);
• R⁴ and R⁵ each independently are hydrogen, halo, Ar¹, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_1-6alkyloxy, C_1-6alkylthio, amino, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl or C_1-6alkylS(O)₂C_1-6alkyl;
• R⁶ and R⁷ each independently are hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxy, Ar²oxy, trihalomethyl, C_1-6alkylthio, di(C_1-6alky)amino, or
  • when on adjacent positions R⁶ and R⁷ taken together may form a bivalent radical of formula
• 
  —O—CH₂—O—  (c-1), or
• 
  —CH═CH—CH═CH—  (c-2);
• R⁸ is hydrogen, C_1-6alkyl, cyano, hydroxycarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylcarbonylC_1-6alkyl, cyanoC_1-6 alkyl, C_1-6 alkyloxycarbonylC_1-6 alkyl, carboxyC_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl, mono- or di(C_1-6alky)aminoC_1-6alkyl, imidazolyl, haloC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, aminocarbonylC_1-6alkyl, or a radical of formula
• 
  —O—R¹⁰  (b-1),
• 
  —S—R¹⁰  (b-2),
• 
  —N—R¹¹R¹²  (b-3),
• • wherein R¹⁰ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹, Ar²C_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, or a radical or formula -Alk²-OR¹³ or -Alk²-NR¹⁴R¹⁵;
    • R¹¹ is hydrogen, C_1-12alkyl, Art or Ar²C_1-6alkyl;
    • R¹² is hydrogen, C_1-6alkyl, C_1-16alkylcarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylaminocarbonyl, Ar¹, Ar²C_1-6alkyl, C_1-6alkylcarbonyl-C_1-6alkyl, a natural amino acid, Ar¹carbonyl, Ar²C_1-6alkylcarbonyl, aminocarbonylcarbonyl, C_1-6alkyloxyC_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy, aminocarbonyl, di(C_1-6alky)aminoC_1-6alkylcarbonyl, amino, C_1-6 alkylamino, C_1-6alkylcarbonylamino,
      • or a radical or formula -Alk²-OR¹³ or -Alk²-NR¹⁴R¹⁵;
      • wherein Alk² is C_1-6alkanediyl;
        • R¹³ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy-C_1-6 alkyl, Ar¹ or Ar²C_1-6 alkyl;
        • R¹⁴ is hydrogen, C_1-6alkyl, Ar¹ or Ar2C_1-6alkyl;
        • R¹⁵ is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, Ar¹ or Ar²C_1-6alkyl;
• R¹⁷ is hydrogen, halo, cyano, C_1-6alkyl, C_1-6alkyloxycarbonyl, Ar¹;
• R¹⁸ is hydrogen, C_1-6alkyl, C_1-6alkyloxy or halo;
• R¹⁹ is hydrogen or C_1-6alkyl;
• Ar¹ is phenyl or phenyl substituted with C_1-6alkyl, hydroxy, amino, C_1-6alkyloxy or halo; and
• Ar² is phenyl or phenyl substituted with C_1-6alkyl, hydroxy, amino, C_1-6alkyloxy or halo.
• In Formulas (I), (II) and (III), R⁴ or R⁵ may also be bound to one of the nitrogen atoms in the imidazole ring. In that case the hydrogen on the nitrogen is replaced by R⁴ or R⁵ and the meaning of R⁴ and R⁵ when bound to the nitrogen is limited to hydrogen, Ar¹, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6 alkyloxyC_1-6 alkyl, C_1-6alkyloxycarbonyl, C_1-6alkylS(O)C_1-6alkyl, C_1-6alkylS(O)₂C_1-6alkyl.
• Preferably the substituent R¹⁸ is situated on the 5 or 7 position of the quinolinone moiety and substituent R¹⁹ is situated on the 8 position when R¹⁸ is on the 7-position.
• Interesting compounds are these compounds of formula (I) wherein X is oxygen.
• Also interesting compounds are these compounds of formula (I) wherein the dotted line represents a bond, so as to form a double bond.
• Another group of interesting compounds are those compounds of formula (I) wherein R¹ is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, di(C_1-6alkyl)aminoC_1-6alkyl, or a radical of formula -Alk¹—C(═O)—R⁹, wherein Alk¹ is methylene and R⁹ is C_1-8alkylamino substituted with C_1-6alkyloxycarbonyl.
• Still another group of interesting compounds are those compounds of formula (I) wherein R³ is hydrogen or halo; and R² is halo, C_1-6alkyl, C_2-6alkenyl, C_1-6alkyloxy, trihalomethoxy or hydroxyC_1-6alkyloxy.
• A further group of interesting compounds are those compounds of formula (I) wherein R² and R³ are on adjacent positions and taken together to form a bivalent radical of formula (a-1), (a-2) or (a-3).
• A still further group of interesting compounds are those compounds of formula (I) wherein R⁵ is hydrogen and R⁴ is hydrogen or C_1-6alkyl.
• Yet another group of interesting compounds are those compounds of formula (I) wherein R⁷ is hydrogen; and R⁶ is C_1-6alkyl or halo, preferably chloro, especially 4-chloro.
• A particular group of compounds are those compounds of formula (I) wherein R⁸ is hydrogen, hydroxy, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyloxy-carbonylC_1-6alkyl, imidazolyl, or a radical of formula —NR¹¹R¹² wherein R¹¹ is hydrogen or C_1-12alkyl and R¹² is hydrogen, C_1-6alkyl, C_1-6alkyloxy, hydroxy, C_1-6alkyloxyC_1-6alkylcarbonyl, or a radical of formula -Alk²-OR¹³ wherein R¹³ is hydrogen or C_1-6alkyl.
• Preferred compounds are those compounds wherein R¹ is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, di(C_1-6alky)aminoC_1-6alkyl, or a radical of formula -Alk¹-C(═O)—R⁹, wherein Alk¹ is methylene and R⁹ is C_1-8 alkylamino substituted with C_1-6alkyloxycarbonyl; R² is halo, C_1-6alkyl, C_2-6alkenyl, C_1-6alkyloxy, trihalomethoxy, hydroxyC_1-6alkyloxy or Ar¹; R³ is hydrogen; R⁴ is methyl bound to the nitrogen in 3-position of the imidazole; R⁵ is hydrogen; R⁶ is chloro; R⁷ is hydrogen; R⁸ is hydrogen, hydroxy, haloC_1-6alkyl, hydroxyC_1-6alkyl, cyanoC_1-6alkyl, C_1-6alkyloxycarbonylC_1-6alkyl, imidazolyl, or a radical of formula —NR¹¹R¹² wherein R¹¹ is hydrogen or C_1-12alkyl and R¹² is hydrogen, C_1-6alkyl, C_1-6alkyloxy, C_1-6alkyloxyC_1-6alkylcarbonyl, or a radical of formula -Alk²-OR¹³ wherein R¹³ is C_1-6alkyl; R¹⁷ is hydrogen and R¹⁸ is hydrogen.
• Most preferred compounds are
• 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,
• 6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;
• 6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone;
• 6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone monohydrochloride.monohydrate;
• 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone,
• (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salt; and
• (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (Compound 75 in Table 1 of the Experimental part of WO-97/21701); or a pharmaceutically acceptable acid addition salt thereof. The latter compound is especially preferred.
• Further preferred embodiments of the present invention include compounds of formula (IX) wherein one or more of the following restrictions apply:
• • ═X¹—X²—X³ is a trivalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9) wherein each R⁶ independently is hydrogen, C_1-4alkyl, C_1-4alkyloxycarbonyl, amino or aryl and R⁷ is hydrogen;
  • >Y¹—Y²— is a trivalent radical of formula (y-1), (y-2), (y-3), or (y-4) wherein each R⁹ independently is hydrogen, halo, carboxyl, C_1-4alkyl or C_1-4alkyloxycarbonyl;
  • r is 0, 1 or 2;
  • s is 0 or 1;
  • t is 0;
  • R¹ is halo, C_1-6alkyl or two R¹ substituents ortho to one another on the phenyl ring may independently form together a bivalent radical of formula (a-1);
  • R² is halo;
  • R³ is halo or a radical of formula (b-1) or (b-3) wherein
    • R¹⁰ is hydrogen or a radical of formula -Alk-OR¹³.
    • R¹¹ is hydrogen;
• R¹² is hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, hydroxy, C_1-6alkyloxy or mono- or di(C_1-6alky)aminoC_1-6alkylcarbonyl;
  • Alk is C_1-6alkanediyl and R¹³ is hydrogen;
  • R⁴ is a radical of formula (c-1) or (c-2) wherein
    • R¹⁶ is hydrogen, halo or mono- or di(C_1-4alky)amino;
    • R¹⁷ is hydrogen or C_1-6alkyl;
  • aryl is phenyl.
• A particular group of compounds consists of those compounds of formula (IX) wherein ═X¹—X²—X³ is a trivalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9), >Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), r is 0 or 1, s is 1, t is 0, R¹ is halo, C_(1-4)alkyl or forms a bivalent radical of formula (a-1), R² is halo or C_1-4alkyl, R³ is hydrogen or a radical of formula (b-1) or (b-3), R⁴ is a radical of formula (c-1) or (c-2), R⁶ is hydrogen, C_1-4alkyl or phenyl, R⁷ is hydrogen, R⁹ is hydrogen or C_1-4alkyl, R¹⁰ is hydrogen or -Alk-OR¹³, R¹¹ is hydrogen and R¹² is hydrogen or C_1-6alkylcarbonyl and R¹³ is hydrogen;
• Preferred compounds are those compounds of formula (IX) wherein ═X¹—X²—X³ is a trivalent radical of formula (x-1) or (x-4), >Y1-Y2 is a trivalent radical of formula (y-4), r is 0 or 1, s is 1, t is O, R¹ is halo, preferably chloro and most preferably 3-chloro, R² is halo, preferably 4-chloro or 4-fluoro, R³ is hydrogen or a radical of formula (b-1) or (b-3), R⁴ is a radical of formula (c-1) or (c-2), R⁶ is hydrogen, R⁷ is hydrogen, R⁹ is hydrogen, R¹⁰ is hydrogen, R¹¹ is hydrogen and R¹² is hydrogen;
• Other preferred compounds are those compounds of formula (IX) wherein ═X¹—X²—X³ is a trivalent radical of formula (x-2), (x-3) or (x-4)>Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R¹ is halo, preferably chloro, and most preferably 3-chloro or R¹ is C_1-4alkyl, preferably 3-methyl, R² is halo, preferably chloro, and most preferably 4-chloro, R³ is a radical of formula (b-1) or (b-3), R⁴ is a radical of formula (c-2), R⁶ is C_1-4alkyl, R⁹ is hydrogen, R¹⁰ and R¹¹ are hydrogen and R¹² is hydrogen or hydroxy.
• The most preferred compounds of formula (IX) are
• 7-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-5-phenylimidazo[1,2-a]quinoline;
• α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-phenylimidazo[1,2-a]quinoline-7-methanol;
• 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)imidazo[1,2-a]quinoline-7-methanol;
• 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)imidazo[1,2-a]quinoline-7-methanamine;
• 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine;
• 5-(3-chlorophenyl)-α-(4-chlorophenyl)-1-methyl-α-(1-methyl-1H-imidazol-5-yl)-1,2,4-triazolo[4,3-a]quinoline-7-methanol;
• 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine;
• 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol; 5-(3-chlorophenyl)-α-(4-chlorophenyl)-4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol;
• 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine;
• 5-(3-chlorophenyl)-α-(4-chlorophenyl)-N-hydroxy-α-(1-methyl-1H-imidazol-5-yl)tetrahydro[1,5-a]quinoline-7-methanamine;
• α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-(3-methylphenyl)tetrazolo[1,5-a]quinoline-7-methanamine; the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof
• 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine, especially the (−) enantiomer, and its pharmaceutically acceptable acid addition salts are especially preferred.
• As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C_1-6alkyl defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; C_1-8alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C_1-6alkyl as well as the higher homologues thereof containing 7 or 8 carbon atoms such as, for example heptyl or octyl; C_1-12alkyl again encompasses C_1-8alkyl and the higher homologues thereof containing 9 to 12 carbon atoms, such as, for example, nonyl, decyl, undecyl, dodecyl; C_1-6alkyl again encompasses C_1-12alkyl and the higher homologues thereof containing 13 to 16 carbon atoms, such as, for example, tridecyl, tetradecyl, pentedecyl and hexadecyl; C_2-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; C_1-6alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof. The term “C(═O)” refers to a carbonyl group, “S(O)” refers to a sulfoxide and “S(O)₂” to a sulfon. The term “natural amino acid” refers to a natural amino acid that is bound via a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of the amino acid and the amino group of the remainder of the molecule. Examples of natural amino acids are glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylanaline, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine.
• The pharmaceutically acceptable acid or base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and non-toxic base addition salt forms which the compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) are able to form. The compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
• The compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) which have acidic properties may be converted in their pharmaceutically acceptable base addition salts by treating said acid form with a suitable organic or inorganic base. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
• The terms acid or base addition salt also comprise the hydrates and the solvent addition forms which the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
• The term stereochemically isomeric forms of compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
• Some of the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
• Whenever used hereinafter, the term “compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX)” is meant to include also the pharmaceutically acceptable acid or base addition salts and all stereoisomeric forms.
• Other farnesyl protein transferase inhibitors which can be employed in accordance with the present include Arglabin, perrilyl alcohol, SCH-66336, 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone (Merck); L778123, BMS 214662, Pfizer compounds A and B described above. These compounds can be prepared, for example, by methods described in the relevant patent specifications identified above which are incorporated herein by reference.
• Farnesyl protein transferase inhibitors can be prepared and formulated into pharmaceutical compositions by methods known in the art and in particular according to the methods described in the published patent specifications mentioned herein and incorporated by reference; for the compounds of formulae (I), (II) and (III) suitable examples can be found in WO-97/21701. Compounds of formulae (IV), (V), and (VI) can be prepared and formulated using methods described in WO 97/16443, compounds of formulae (VII) and (VIII) according to methods described in WO 98/40383 and WO 98/49157 and compounds of formula (IX) according to methods described in WO 00/39082 respectively. To prepare the aforementioned pharmaceutical compositions, a therapeutically effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous, or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. Application of said compositions may be by aerosol, e.g. with a propellent such as nitrogen, carbon dioxide, a freon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.
• It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
• Preferably, a therapeutically effective amount of the pharmaceutical composition comprising a farnesyl protein transferase inhibitor is administered orally or parenterally. Said therapeutically effective amount is the amount that effectively prevents growth or reduces the size of breast cancer tumors in patients. On the basis of the current data, it appears that a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), and in particular (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (compound 75) as the active ingredient can be administered orally in an amount of from 10 to 1500 mg daily, either as a single dose or subdivided into more than one dose. A preferred amount ranges from 100 to 1,000 mg daily. A particularly preferred dosage for such a compound is 300 mg administered twice daily. This treatment can be given either continuously or intermittently in cycles of 3-4 weeks with treatment given for 1-21 days per cycle.
• Suitable dosages for the compounds Arglabin (WO98/28303), perrilyl alcohol (WO 99/45712), SCH-66336 (U.S. Pat. No. 5,874,442), L778123 (WO 00/01691), 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3 (S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone (WO94/10138), BMS 214662 (WO 97/30992), Pfizer compounds A and B (WO 00/12499 and WO 00/12498) are given in the aforementioned patent specifications which are incorporated herein by reference or are known to or can be readily determined by a person skilled in the art.
• In relation to perrilyl alcohol, the medicament may be administered 1-4 g per day per 150 lb human patient. Preferably, 1-2 g per day per 150 lb human patient. SCH-66336 typically may be administered in a unit dose of about 0.1 mg to 100 mg, more preferably from about 1 mg to 300 mg according to the particular application. Compounds L778123 and 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone may be administered to a human patient in an amount between about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day, preferably between 0.5 mg/kg of bodyweight to about 10 mg/kg of body weight per day.
• Pfizer compounds A and B may be administered in dosages ranging from about 1.0 mg up to about 500 mg per day, preferably from about 1 to about 100 mg per day in single or divided (i.e. multiple) doses. Therapeutic compounds will ordinarily be administered in daily dosages ranging from about 0.01 to about 10 mg per kg body weight per day, in single or divided doses. BMS 214662 may be administered in a dosage range of about 0.05 to 200 mg/kg/day, preferably less than 100 mg/kg/day in a single dose or in 2 to 4 divided doses.
• The above farnesyl transferase inhibitor may be used in combination with one or more other treatments for advanced breast cancer especially endocrine therapy such as an anti-estrogen agent such as an estrogen receptor antagonist or a selective estrogen receptor modulator or an aromatase inhibitor. A particularly preferred estrogen receptor antagonist is tamoxifen which has previously been widely used in the treatment of breast cancer. Other estrogen receptor antagonists or selective estrogen receptor modulators include toremifene, droloxifene, faslodex and raloxifene. Examples of aromatase inhibitors or inactivators include exemestane, anastrozole, letrazole and vorozole. Other anti-cancer agents which may be employed include platinum coordination compounds for example cisplatin or carboplatin, taxane compounds for example paclitaxel or docetaxel, camptothecin compounds for example irinotecan or topotecan, anti-tumor vinca alkaloids for example vinblastine, vincristine or vinorelbine, anti-tumor nucleoside derivatives for example 5-fluorouracil, gemcitabine or capecitabine, nitrogen mustard or nitrosourea alkylating agents for example cyclophosphamide, chlorambucil, carmustine or lomustine, anti-tumor anthracycline derivatives for example daunorubicin, doxorubicin, idarubicin or epirubicin; HER2 antibodies for example trastzumab; and anti-tumor podophyllotoxin derivatives for example etoposide or teniposide.
• The farnesyl transferase inhibitor and the further anti-cancer agent may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular farnesyl transferase inhibitor and further anti-cancer agents being administered, their route of administration, the particular tumor being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.
Clinical Study
• Compound 75 above, namely (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone was tested in patients with advanced breast cancer as described in the following account of a clinical study.
• The clinical study involved 27 patients with advanced breast cancer. The median age of the patients was 59 years (range 35-80 years). Adjuvant chemo and/or endocrine therapy had been received by 15 and 16 patients respectively. Prior therapy for advanced disease included second-line hormonal therapy in 18 (67%) patients and/or one chemotherapy regimen only in 14 (52%) patients. Treatment was well tolerated, with myelosuppression the most frequent and dose-limiting toxicity. The first 6 patients treated with 400 mg of compound 75 b.i.d. developed grade ¾ neutropenia after a median of 26 days; 5 were re-treated with dose reduction following neutrophil recovery without further haematological toxicity. The subsequent 21 patients received 300 mg of compound 75 b.i.d.; 6 (29%) developed grade ¾ neutropenia after a median of 32 days, with one episode of fever. Neutrophil recovery occurred over 1-2 weeks in all cases. Thrombocytopenia (grade 3) occurred in 3 (11%) patients. Non-haematological toxicities included: grade ⅔ parasthesia/numbness in 7 (26%) patients occurring after a median of 10 weeks therapy; grade ⅔ diarrhoea in 3 (11%) patients; skin rash in 3 (11%); fatigue in 8 (28%). 26 patients were able to be evaluated for tumour response; 8 withdrew early (<12 weeks) due to either progression of disease and/or toxicity while 18 patients received at least 3 months treatment (range 12-36+ weeks). Tumour shrinkage of at least 50% in volume was seen in 3 (12%) patients, sites of response included liver, lung, lymph nodes and skin nodules. A further 9 (35%) patients had stable disease, i.e. no progression of tumour growth, at the 3 month evaluation. These results demonstrated that compound 75 has clinical activity in advanced breast cancer.

Claims (3)

1-13. (canceled)

14. A method of treating advanced breast cancer in a mammal comprising administering orally to said mammal the compound (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)-1-methyl-2(1H)-quinolinone or a pharmaceutically acceptable acid addition salt thereof, in a dosage amount of 300 mg twice daily.

15. The method of claim 14 in which the compound is administered in combination with tamoxifen.